Osteointegrative interface for implantable prostheses and a method for the treatment of the osteointegrative interface

ABSTRACT

A biomimetic osteointegrative interface comprising a substrate of biocompatible material such as titanium, tantalum or their alloys comprising, on the surface of the substrate, a first layer having a first concentration of oxide of the biocompatible material, enriched with a second concentration of phosphorus and with a third concentration of calcium, the ratio between the concentration of calcium and the concentration of phosphorus being greater than two. The biomimetic osteointegrative interface further comprises a second layer having a first surface in contact with the first layer and a second surface. The second layer has a fourth concentration of oxide enriched with a fifth concentration of calcium and a sixth concentration of phosphorus. The fourth concentration is less than the fifth and sixth concentrations and the ration between the fifth concentration of calcium and the sixth concentration of phosphorus is no less than three.

DESCRIPTION

The present invention relates to an osteointegrative interface forimplantable prostheses and to a method for the treatment of theosteointegrative interface, particularly to a biomimeticosteointegrative interface and to a method for modifying the surface ofthe osteointegrative interface superficially.

Biomimetic processes which simulate biomineralization processes havebeen used with success for preparing materials such as iron oxides,apatite, and cadmium sulphide which are used in various technologicalfields.

The field which has drawn most “inspiration” from biomineralizationprocesses is the field of biomaterials and, in particular, biomaterialsfor orthopaedics, maxillo-facial surgery, and dentistry.

These materials have to interact with body tissues and should thereforepossess particular biocompatibility and bioactivity qualities andmechanical properties.

The main uses of biomaterials in the hard tissues field includeprostheses such as hip prostheses, knee prostheses, dental implants,screws, nails, plates and osteosynthesis means.

Because of the mechanical properties required, the materials usuallyused for prostheses are stainless steel, titanium, titanium alloys, andtantalum, which have the best biocompatibility characteristics of all ofthe metals.

These metals exhibit a high mechanical breaking load but require longimplantation periods in order for their integration with the biologicaltissues such as, for example, bone, to be established.

To prevent this problem, there are known biomimetic treatments forosteointegrative interfaces, by means of which it is possible to bringabout a significant increase in the rate of precipitation ofhydroxyapatite after immersion in biological fluids, and its adhesion tothe prosthesis.

Calcium phosphates, including hydroxyapatite, are the main constituentsof the inert bone matrix.

U.S. Pat. No. 5,152,993 (Lars Magnus et al.) and U.S. Pat. No. 5,885,612(Ohthuke et al.) propose a treatment in hydrogen peroxide with the useof hydrogen peroxide or hydrogen peroxide and metal ions, which modifiesthe surface of the prosthesis, promoting the formation of —OH hydroxylfunctional groups which can induce the formation of a stable interfacewith bone.

U.S. Pat. No. 5,609,633 (Kokubo) and the corresponding application EP678300A1 (Kokubo) teach a treatment based on immersion in an alkalinesolution such as NaOH, KOH or CaOH₂, followed by washing andhigh-temperature heat treatment.

In particular, these two documents describe a treatment for etching withhydroxides an oxide such as titanium oxide, which is almost completelycrystalline and is composed mainly of the rutile, anastase and, rarely,brookite phases, which are different crystalline forms of titaniumdioxide, that is TiO₂.

This etching has the advantage not only of forming a larger number of—OH groups so that the surface layer hydroxylates more easily and isparticularly significantly enriched with oxygen, but also of achievingthe formation of a layer of amorphous calcium phosphates which arestoichiometrically similar to hydroxyapatite and can therefore promotethe formation of mature hydroxyapatite.

The heat treatment included in this treatment with alkalis would lead toan increase of up to about 1 μm in the thickness of the titanium oxidelayer.

To achieve a significant increase in the thickness of oxide which formson the surface of a metal, anodic passivation treatments have beenoptimized by the development of a technique known as anodic sparkdeposition (ASD).

The ASD technique is a galvanic electrodeposition process which isperformed at fairly high voltage and which causes point breakdown andperforation of the dielectric surface oxide layer which is formedprogressively, thus allowing it to grow.

With this technique, as described, for example, in U.S. Pat. No.5,385,662 (Kurze et al.), it is possible to produce coatings with thecharacteristics of sintered ceramic materials, which are particularlyresistant to abrasion and corrosion, and with thicknesses of up to 150μm.

With specific reference to bone implants, U.S. Pat. No. 5,478,237(Ishizawa) teaches the use of this technique to bring about amodification of the composition, of the thickness, and of the morphologyof the titanium oxide film, that is, the formation of a thick andnanoporous oxide film containing calcium and phosphorus, of a thicknessclearly greater than that which is formed by natural oxidation of themetal.

However, this technique does not substantially improve the biomimeticproperties of the titanium.

In order to improve its biomimetic capacity, the film or layer issubjected to a hydrothermic treatment which can promote nucleation ofhydroxyapatite crystals. However, these crystals are not distributedhomogeneously and do not cover the surface of the osteointegrativeinterface completely.

Homogeneity of behaviour is therefore not achieved.

Moreover, the mechanical bond between oxide and crystals is very weak.

In view of the prior art described, the object of the present inventionis to modify superficially the surface of titanium, of tantalum, and oftheir alloys so as to produce biomimetic surfaces having structural andmorphological characteristics that are innovative in comparison withthose known from the prior art.

According to the present invention, this object is achieved by abiomimetic osteointegrative interface according to claim 1.

This object is also achieved by a method for the production of abiomimetic osteointegrative interface according to claim 4.

By virtue of the present invention, it is possible to achieve anincrease in the thickness of the oxide film of titanium, of tantalum, orof their alloys from a few nanometres to a few micrometres by reducing,amongst other things, the extent to which metal ions are released fromthe implant. The adhesion of the oxide layer to the substrate isexcellent.

The present invention, also enables elements such as calcium andphosphorus which can promote mineralization processes of theextxacellular bone matrix to be incorporated in the oxide film oftitanium, of tantalum, or of their alloys.

Moreover, by virtue of the present invention it is possible to bringabout, for example, in a sponge, the formation of nanometric porositywhich can geometrically promote protein adhesion and consequently theadhesion of osteoblast cells.

Finally, by virtue of the present invention, it is possible to bringabout the creation, within the titanium oxide film, that is, in itsporosity, of -OH bonds which can form chemical bonds both with calciumand phosphorus ions, further promoting the mineralization of theextracellular matrix, and with proteins, further promoting osteoblastadhesion.

The characteristics and the advantages of the present invention willbecome clear from the following detailed description of a practicalembodiment thereof which is illustrated by way of non-limiting examplein the appended drawing, in which:

FIG. 1 shows, in section, an embodiment of an osteointegrative interfaceaccording to the present invention, and

FIG. 2 is a section, taken on the line II-II, of the layers making upthe surface of the osteointegrative interface of FIG. 1.

One of the most important requirements in applications forosteointegrative interfaces is to synthesize a surface with crystals ofdimensions comparable to those of biological apatite, so that anincrease in the surface area of the crystals can improve theinteractions at the interface with the bone tissue and increase thecapability of the material thus to create a bond with the bone tissue.

With reference to appended FIGS. 1 and 2, which show an example of anosteointegrative interface for a dental implant 1 according to thepresent invention, this requirement is satisfied.

With reference in particular to FIG. 2, an enlarged section through theimplant 1, taken on the line II-II of FIG. 1 so as to show the layersmaking up the surface of the osteointegrative interface 1, is indicated2.

These layers comprise a substrate 3 generically of titanium, aprotective layer 4, generically of titanium oxide, superimposed on thesurface 3 bis of the substrate 3, and a surface layer 5 superimposed onthe protective layer 4.

FIG. 1 shows the dental implant 1 which has, for example, the shape of ascrew, and which has been inserted in a bone socket 6; a tooth crown isindicated 7 and the gum is indicated 8.

Naturally, the shape and size of the implant must be selected independence on the specific application and the example shown in FIG. 1is only one of the possible embodiments.

In particular, the substrate 3 which constitutes the core of the dentalimplant 1 is composed of transition metals, for example, of titanium, oftantalum, or of their alloys.

If the substrate 3 is made of titanium, the protective layer 4 willcomprise titanium oxide which is formed by the process described belowto reach a thickness of the order of a few μm, for example 5-1.0 μm.

In the innovative embodiment, this protective layer 4 is enrichedthroughout its thickness of 5-1.0 μm with a relatively uniform and highconcentration of elements such as calcium and phosphorus, theconcentration of the element calcium being greater than theconcentration of phosphorus, for example, more than 2 times greater,that is Ca/P>2.

The surface layer 5, which has a thickness of the order of tens ofnanometres and is superimposed on the protective layer 4, comprises thesame elements as the protective layer 4 but these elements haveconcentration ratios between calcium and titanium, that is Ca/Ti, andbetween phosphorus and titanium, that is P/Ti, which tend to be greatlyin favour of the elements which constitute the enrichment, that is(Ca+P)/Ti>80%. Moreover the Ca/P ratio is higher and is equal to aboutCa/P≅3 or even more.

Moreover, it can be seen that the surface layer 5 has a lower surface 10and an upper surface 11, the lower surface 10 being in contact with thetitanium oxide layer 4 and the S upper surface 11 being in contact withthe bone socket 6. The layer 5, particularly on the upper surface 11, isalso characterized by the presence of a high concentration of —OHchemical coupling groups, suitable for forming a plurality of nucleationcentres 12.

The osteointegrative interface thus described is produced by a series ofsteps which are described below.

In a first step, the surface 3 bis of the implant 1 is subjected to amechanical or even chemical finishing treatment with abrasive paper,sandblasting, or the like, to produce a surface with controlled andhomogeneous roughness with Ra values of the order of 1-2 μm for dentalimplants and greater values for non-cemented orthopaedic prostheses.

There is then a second step of cleaning of the upper surface 3 bis withthe use, for this purpose, of an ultrasound chamber containing acetonefor a first period of time included within a time interval where 3<t<5minutes and distilled water for a second period of time, where 3<t<5minutes.

This step is useful since it enables dirt particles and/or impurities tobe removed from the surface 3 bis of the substrate 3.

A third step is then provided for; in this step a first anodic sparkdeposition (ASD) treatment takes place in an aqueous calciumglycerophosphate (Ca-GP) solution at a concentration of 0.015 M with amaximum variation of about ±0.005M. This step provides for treatment atabout T=0° C., preferably with a maximum variation of ±1° C. and with apredetermined current-intensity value of about 70 A/M², whilst thepotential rises freely to a predetermined final value of about 350 V.This brings about the growth of the protective layer 4 and thedeposition therein of a predetermined quantity of phosphorus and alsosome calcium.

The mechanical adhesion of the protective layer to the substrate isoutstanding.

The third step ends when the potential reaches 350 V and the currentintensity is still about 70 A/M².

A fourth step is then performed in which washing in distilled water andcareful drying of the osteointegrative implant 1 thus treated takeplace.

The fifth step provides for a second ASD treatment in an aqueoussolution of calcium hydroxide └Ca(OH)₂┘ at a concentration of 0.1 M witha maximum variation of ±0.02M. For a first period of time, the treatmentis performed at a temperature of between two and eight degreescentigrade, that is 2° C.<T<8° C., with a constant current intensity ofabout 70 A/m² whilst the potential is allowed to rise to a final valueof about 370 V.

The fifth step continues for a second period of time with deposition ata constant voltage of about 370 V and simultaneous reduction in currentto a predetermined value of about 35 A/M².

The layer 4 is thus modified and incorporates further calcium.

It should be noted that the final current intensity is equal to half ofthe initial current used during the first stage of the second ASDtreatment.

There is then a sixth step which provides for further washing indistilled water and careful drying of the implant 1 thus treated.

The seventh step provides for the immersion of the osteointegrativeimplant 1 thus treated in 5 M aqueous KOH solution (or even NaOH, butwith less satisfactory results) kept at T=60° C. for t=24 h.

Finally, an eighth step is provided for; in this step a final washing indistilled water and careful drying of the interface thus treated takeplace.

In particular, it should be noted that the third step, that is the firstASD, produces a titanium oxide layer 4 which is rich in phosphorus andpartially in calcium so as to give rise to a dielectric with a thicknessof the order of a few μm (possibly about ten μm) which permits theapplication of the high voltages that are required in the second ASD.

In fact, without a first deposition and thickening of the surface oxide,it is impossible to bring the osteointegrative implant 1 to a voltagehigh enough to perform the second ASD treatment in Ca(OH)₂ solution,which is a solution without anions such as to be able to ensure theformation of an adequate dielectric thickness.

Basically, whereas with the first ASD a titanium oxide layer of thedesired thickness, provided with a first concentration of calcium andphosphorus, is formed, with the second ASD treatment, the layer isthickened and there is an increase in the Ca/P ratio.

Moreover, the second ASD treatment is preparatory to the formation ofnucleation centres characterized by the presence of surface —OH chemicalgroups.

The seventh step, that is, the immersion of the interface 1 in a KOHsolution, further increases the Ca/P ratio, since phosphorus isextracted from the surface portion of the layer 4 so as to favour itshydration and a high concentration of —OH groups is produced on thesurface.

The fifth step and the seventh step thus produce a surface layer 5 inwhich the Ca/Ti and P/Ti ratios tend to be greatly in favour of the twoelements which constitute the enrichment, to the extent that the surfacelayer 5 is composed, in its last nanometres, substantially by calciumand phosphorus, with a Ca/P ratio close to four and in any case no lessthan three.

Moreover, by virtue of the innovative treatment method, the surfacelayer 5 is rich in —OH chemical coupling groups which favour thedeposition of calcium and phosphorus in a physiological solution.

Although, in the description, reference is made specifically to titaniumosteointegrative interfaces, clearly the invention put forward is alsoapplicable to interfaces made of tantalum and of alloys of titanium andof tantalum.

1. A biomimetic osteointegrative interface comprising a substrate (3) ofbiocompatible material such as titanium, tantalum, or their alloys,comprising, on the surface (3 bis) of the substrate (3), a first layer(4) having a first concentration of oxide of the biocompatible material,enriched with a second concentration of phosphorus and with a thirdconcentration of calcium, the ratio between the concentration of calciumand the concentration of phosphorus being greater than two, thebiomimetic osteointegrative interface (1) further comprising a secondlayer (5) having a first surface (10) in contact with the first layer(4), and a second surface (11), the second layer (5) having a fourthconcentration of oxide enriched with a fifth concentration of calciumand a sixth concentration of phosphorus, the fourth concentration beingless than the fifth and sixth concentrations and the ratio between thefifth concentration of calcium and the sixth concentration of phosphorusbeing no less than three.
 2. The biomimetic osteointegrative interfaceaccording to claim 1, wherein the second layer (5) has a gradient of thefifth calcium concentration and of the sixth phosphorus concentrationwhich gradient increases from the first surface (10) towards the secondsurface (11) of the second layer (5).
 3. The biomimetic osteointegrativeinterface according to claim 2, wherein the second layer (5) is hydratedand has —OH hydroxyl chemical coupling groups suitable for forming aplurality of nucleation centers (12).
 4. A method for the biomimetictreatment of an osteointegrative interface on a substrate ofbiocompatible metal such as titanium, tantalum, or their alloys,comprising the following steps: a) performing a first ASD anodicdeposition treatment of the osteointegrative interface (1) in a calciumglycerophosphate solution, b) performing a second ASD anodic depositiontreatment of the osteointegrative interface (1) in a calcium hydroxidesolution, and c) performing an immersion of the osteointegrativeinterface (1) in a potassium hydroxide solution.
 5. The method for thebiomimetic treatment of an osteointegrative interface according to claim4, wherein the electrolytic solution containing calcium glycerophosphatehas a concentration of 0.015±0.005 M and a temperature T within a rangewhere −1° C. <T<+1° C.
 6. The method for the biomimetic treatment of anosteointegrative interface according to any one of claim 4, wherein thefirst ASD deposition takes place with a constant current equal to afirst predetermined value and with a voltage increasing freely to afirst final value.
 7. The method for the biomimetic treatment of anosteointegrative interface according to claim 6, wherein the first finalvoltage value is equal to about 350 V.
 8. The method for the biomimetictreatment of an osteointegrative interface according to claim 6, whereinthe first predetermined current value is equal to about 70 A/m².
 9. Themethod for the biomimetic treatment of an osteointegrative interfaceaccording to any one of claim 4, wherein the electrolytic solutioncontaining calcium hydroxide has a concentration of 0.1±0.02 M and atemperature T within a range where 2° C.<T<8° C.
 10. The method for thebiomimetic treatment of an osteointegrative interface according to anyone of claim 4, wherein the second ASD anodic deposition provides, for afirst period of time, for a constant current equal to a secondpredetermined current value and for a voltage increasing freely to asecond final value, and further provides, for a second period of time,for a current decreasing freely to a third value and for a constantvoltage equal to a third predetermined voltage value.
 11. The method forthe biomimetic treatment of an osteointegrative interface according to10, wherein the second predetermined current value is equal to about 70A/m².
 12. The method for the biomimetic treatment of an osteointegrativeinterface according to claim 10, wherein the second and third finalvoltage values are identical and are equal to about 370 V.
 13. Themethod for the biomimetic treatment of an osteointegrative interfaceaccording to any one of claim 4, wherein the immersion in potassiumhydroxide solution takes place for a period of at least t=24 hours and atemperature T within a range where 59° C<T<61° C.
 14. A method for thebiomimetic treatment of an osteointegrative interface on a substrate ofbiocompatible metal such as titanium, tantalum, or their alloys,comprising the following steps: a) performing a first ASD anodicdeposition treatment of the osteointegrative interface (1) in a calciumglycerophosphate solution, b) performing a second ASD anodic depositiontreatment of the osteointegrative interface (1) in a calcium hydroxidesolution, and c) performing an immersion of the osteointegrativeinterface (1) in a sodium hydroxide solution.
 15. The method for thebiomimetic treatment of an osteointegrative interface according to claim14, wherein the electrolytic solution containing calciumglycerophosphate has a concentration of 0.015±0.005 M and a temperatureT within a range where −1° C.<T<+1° C.
 16. The method for the biomimetictreatment of an osteointegrative interface according to any one of claim14, wherein the first ASD deposition takes place with a constant currentequal to a first predetermined value and with a voltage increasingfreely to a first final value.
 17. The method for the biomimetictreatment of an osteointegrative interface according to claim 16,wherein the first final voltage value is equal to about 350 V.
 18. Themethod for the biomimetic treatment of an osteointegrative interfaceaccording to 16, wherein the first predetermined current value is equalto about 70 A/m².
 19. The method for the biomimetic treatment of anosteointegrative interface according to any one of claim 14, wherein theelectrolytic solution containing calcium hydroxide has a concentrationof 0.1±0.02 M and a temperature T within a range where 2° C.<T<8° C. 20.The method for the biomimetic treatment of an osteointegrative interfaceaccording to any one of claim 14, wherein the second ASD anodicdeposition provides, for a first period of time, for a constant currentequal to a second predetermined current value and for a voltageincreasing freely to a second final value, and further provides, for asecond period of time, for a current decreasing freely to a third valueand for a constant voltage equal to a third predetermined voltage value.21. The method for the biomimetic treatment of an osteointegrativeinterface according to claim 20, wherein the second predeterminedcurrent value is equal to about 70 A/m².
 22. The method for thebiomimetic treatment of an osteointegrative interface according to claim20, wherein the second and third final voltage values are identical andare equal to about 370 V.
 23. The method for the biomimetic treatment ofan osteointegrative interface according to claim 20, wherein the thirdpredetermined current value is equal to half of the second predeterminedcurrent value and is equal to about 35 A/m².